Our laboratories have identified, as the molecular target both necessary and sufficient for low-dose cell killing by poiyphenolic botanicals, a cancer-specific (alternatively spliced) member of an ECTO-NOX family of cell surface hydroquinone or NADH oxidases with protein disulfide-thiol interchange activity designated tNOX. The work proposed will use the target tNOX protein to identify synergies between complex botanicals containing EGCg and other green tea catechins and between green tea catechins and Caps/cum-based botanicals containing vanilloids such as capsaicin and vanillylamine. The goal is to develop food grade decaffeinated green tea-Caps/cum-containing complex botanicals that are at least 100 times more potent on a weight basis than green tea alone and that have an improved therapeutic index (margin of safety). ECTONOX proteins, as a family, are essential for cells to enlarge following their division. When tNOX is blocked (as for example by polyphenol-containing botanical supplements), cells once having divided, fail to enlarge and never reach the minimum size required for the cells to divide again. The resultant small cells, arrested in d and unable to divide, then undergo a cell surface sphingomyelinase/ceramide/sphingosine kinase/FAS apoptotic cascade. Work proposed is focused on inhibition of the tNOX target by polyphenols that results in cancer cell-specific cytotoxicity leading to cancer regression. We propose to analyze and identify the active Capsicum constituents that interact synergistically with the green tea catechins as an important new direction toward development of more efficacious complex anticancer botanicals. Also to be investigated is how ECTO-NOX proteins mediate reactions essential to cell enlargement using recombinant tNOX proteins and X-ray and spectroscopic methods, The expectations are that the studies proposed will result in specific green tea-catechin-Caps/cum (or other polyphenol/proanthocyanadin) combinations with improved anticancer activity that target selectively to tNOX. By selective targeting to tNOX, the opportunity arises for a high degree of cancer specificity and low or no toxicity since normal cells and tissues lack the tNOX polyphenol target.